The stilbenes resveratrol, pterostilbene and piceid affect growth and stress resistance in mammalian cells via a mechanism requiring estrogen receptor beta and the induction of Mn-superoxide dismutase

The mitochondrial antioxidant enzyme, Mn superoxide dismutase (MnSOD), has been shown to confer cytoprotection and to regulate cell cycle progression. Resveratrol, a phytoestrogen found in red wines and other foods, has been previously reported to increase MnSOD protein levels and activity both in vitro and in vivo. Numerous structural analogues of resveratrol produced via the same stilbene synthesis pathway (e.g. pterostilbene and piceid) and also present in foods and red wine may be capable of eliciting the same effects. Furthermore, in humans resveratrol is rapidly metabolized to resveratrol-4'-sulfate, resveratrol-3-glucuronide and other metabolites in vivo. Although these metabolites may accumulate to relatively high levels in plasma and tissues, little is known about their biological activities. Here the activities were compared of these stilbenes and stilbene metabolites in mammalian cells. Two key cellular activities associated with resveratrol were examined: inhibition of proliferative growth and increased stress resistance (important anti-cancer and cell protective activities, respectively). While resveratrol-4'-sulfate and resveratrol-3-glucuronide had no effect on either cell growth or stress resistance, both pterostilbene and piceid were at least as effective as resveratrol. Using pharmacological and genetic approaches, it was found that the effects of pterostilbene and piceid required an induction of the mitochondrial enzyme MnSOD and intact mitochondrial respiration. In addition, using estrogen receptor beta (ERbeta) knockout mouse myoblasts, it was demonstrated that the effects of stilbene compounds on cell growth and stress resistance all require ERbeta. Taken together, these results indicate that resveratrol, pterostilbene and piceid all activate the same mitochondrial response in mammalian cells, and therefore these latter two molecules might be as effective as resveratrol in eliciting positive health outcomes in vivo. (C) 2013 Elsevier Ltd. All rights reserved.